The current U.S. and European guidelines recommend antiplatelet therapy such as aspirin, clopidogrel, or dual antiplatelet therapy to reduce the risk of recurrent ischemic events in patients with noncardioembolic ischemic stroke. However, selection of antiplatelet agents can be a difficult decision to make for older patients. Not only older individuals are at increased risk for recurrent strokes, they also face risk for bleeding complications. While it is known that drug selection should be individualized, it remains unknown how to tailor antiplatelet therapy according to patient unique characteristics, preferences, needs, and values. The long-term goal is to use com- parative effectiveness research to improve primary and secondary prevention in cardiovascular disease and stroke. Leveraging the American Heart Association (AHA) Get With The Guidelines Stroke (GWTG) registry and Medicare claims, the overall objective in this application is to develop patient-centered evidence-based strategies to improve antiplatelet treatment selection for older individuals presenting with noncardioembolic ischemic stroke. The central hypothesis is that individuals differ in many characteristics, such as age, sex, presence of comorbid- ities, or concurrent medications, which can influence the potential benefits and harms associated with the treat- ment. Once the variability in response to treatment is known, selection of an antiplatelet agent can be made based on patient risk profiles, preferences, and known efficacy/safety of the agents, making treatment both safer and more effective. Guided by strong preliminary data, this hypothesis will be tested by pursuing three specific aims: 1) determine the long-term clinical effectiveness of different antiplatelet regimens in patients with noncar- dioembolic ischemic stroke; 2) determine the long-term safety of different antiplatelet regimens; and 3) balance benefits and harms of each antiplatelet regimen while incorporating patient preferences into decision-making. The proposed research is innovative in four key ways: 1) a patient-centered approach is used to address a real- life decisional dilemma facing stroke survivors and clinicians; 2) it shifts focus from selected samples in clinical trials to nationwide representative stroke population, including traditionally underrepresented subgroups in com- munity practice; 3) novel propensity score inverse probability weighting method using generalized boosted mod- els (a machine learning technique) will be employed to mimic a trial-type multi-treatment design, uncover treat- ment heterogeneity, and minimize selection bias in observational data; 4) beyond traditional mechanisms of scientific publications, the evidence generated from this study will be disseminated to stroke survivors, clinicians, and relevant stakeholders through the AHA GWTG-led national quality initiatives and patient-led efforts to insure a rapid translation of seminal findings into clinical practice. The proposed research is significant, because it is expected to help guide personalized antiplatelet therapy in older ischemic stroke survivors that could best meet their needs and lead to better outcomes most meaningful to patients. Ultimately, such knowledge has the poten- tial to inform evidence-based treatment decisions in stroke that now afflicts more than 7.2 million Americans.